ACS Medicinal Chemistry Letters最新文献

Provided herein are novel pyrrolidinone derivatives as NIK inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune and inflammatory diseases, and processes for preparing such compounds.

Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.

A systematic structure–activity relationship study of the potent anticancer marine macrolide biselyngbyolide B has been accomplished. A total of 11 structural variants of the parent natural product, of which 2 are natural analogues, have been studied against a human colorectal carcinoma cell line. The requisite functional units of the parent molecule responsible for the cytotoxic activities have been disclosed. Biselyngbyolide C, one of the natural analogues of biselyngbyolide B, has been studied in depth to explore its molecular mechanism. Interestingly, the in vitro data demonstrated an induction of dynamin-related protein 1-mediated mitochondrial fission and reactive oxygen species production which led to activation of ASK1/P38/JNK-mediated apoptosis in colon cancer cells as an important pathway for biselyngbyolide B-mediated cytotoxicity. Notably, this study revealed that a macrolide participated in mitochondrial fission to promote apoptosis of cancer cells, providing new insight.

Herein we describe the medicinal chemistry efforts that led to the discovery of the clinical-staged Syk inhibitor sovleplenib (41) via a structure–activity relationship investigation and pharmacokinetics (PK) optimization of a pyrido[3,4-b]pyrazine scaffold. Sovleplenib is a potent and selective Syk inhibitor with favorable preclinical PK profiles and robust anti-inflammation efficacy in a preclinical collagen-induced arthritis model. Sovleplenib is now being developed for treating autoimmune diseases such as immune thrombocytopenic purpura and warm antibody hemolytic anemia as well as hematological malignancies.

Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated metabolic diseases make it a potential therapeutic target. However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors. Here, we aimed to identify small-molecule compounds that directly bind to SREBP-1 using the recombinant N-terminal region of SREBP-1a, which is required for its transcriptional activity. A high-throughput screening campaign was conducted using a thermal shift assay and surface plasmon resonance assay to evaluate the compound affinity and specificity, which resulted in the identification of two compounds. Future analysis of their structure–activity relationships may lead to the development of specific SREBP-1 inhibitors, thereby potentially validating SREBP-1 as a therapeutic target for obesity and resultant atherosclerotic diseases.

To facilitate studies of engagement of protein targets by small molecules in living cells, we synthesized fluorinated derivatives of the fluorophore 7-hydroxycoumarin-3-carboxylic acid (7OHCCA). Compared to the related difluorinated coumarin Pacific Blue (PB), amide derivatives of 6-fluoro-7-hydroxycoumarin-3-carboxylic acid (6FC) exhibited substantially brighter fluorescence. When linked to the anticancer drug paclitaxel (Taxol) via gamma-aminobutyric acid (GABA), the acidity of the phenol of these coumarins profoundly affected cellular efflux and binding to microtubules in living cells. In contrast to the known fluorescent taxoid PB-GABA-Taxol, the less acidic 6FC-GABA-Taxol was more cell-permeable due to a lower susceptibility to active efflux. In living cells, this facilitated the imaging of microtubules by confocal microscopy and enabled quantification of binding to microtubules by flow cytometry without added efflux inhibitors. The photophysical, chemical, and biological properties of 6FC derivatives make these compounds particularly attractive for the construction of fluorescent molecular probes suitable for quantitative analysis of intracellular small molecule–protein interactions.

Previously we identified a non-nucleotide agonist BDW568 that selectively activates the human STING^A230 allele. Here, we further characterized the mechanism of BDW568 and highlighted its potential use for selectively controlling the activation of engineered macrophages that constitutively express STING^A230 as a genetic adjuvant. We obtained the crystal structure of the C-terminal domain of STING^A230 complexed with BDW-OH (active metabolite) at 1.95 Å resolution. Structure–activity relationship studies revealed that all three heterocycles in BDW568 and the S-acetate side chain are critical for retaining activity. We demonstrated that BDW568 could robustly activate type I interferon signaling in purified human primary macrophages that were transduced with lentivirus expressing STING^A230. In contrast, BDW568 could not stimulate innate immune responses in human primary peripheral blood mononuclear cells in healthy donors in the absence of a STING^A230 allele. This high STING variant specificity suggested a promising application of STING^A230 agonists in macrophage-based therapeutic approaches.

Provided herein are novel myeloperoxidase inhibitors, pharmaceutical compositions, use of such compounds in treating inflammatory, cardiovascular, respiratory, renal, hepatic, and neurological diseases, cancer, and neutrophilic-driven diseases, and processes for preparing such compounds.